tbuckley/cabot-search huggingface dataset:
TMET-03. STEAROYL-COA DESATURASE INHIBITOR SUPPRESSES IDH MUTANT GLIOMA GROWTH VIA ENHANCING LIPOLYSIS
Authors: Tomohiro Yamasaki, Adrian Lita, Lumin Zhang, Tyrone Dowdy, Shinichiro Koizumi, Kazuhiko Kurozumi, Mark Gilbert, Mioara Larion
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Mutant isocitrate dehydrogenase (IDH) produces 2-hydroxyglutarate (D2HG) and causes metabolic reprograming, but so far, little is known about the role of mutant IDH and D2HG in de novo lipogenesis and fatty acids synthesis. In this study, to develop a feasible drug for IDH mutant glioma, we targeted Stearoyl-CoA desaturase 1 (SCD1) catalyzing the biosynthesis of monosaturated fatty acids (MUFA) to suppress IDH mutant glioma progression. Materials and METHODS We prepared genetically engineered glioma cell lines (U251 wild type: U251WT and U251 IDHR132H mutant: U251RH), normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH) and patient derived cell lines. Lipid metabolic analysis was conducted by using LC-MS, and functional analysis for the role of SCD1 expression was investigated by RNA sequence and Western-blotting. RESULTS LC-MS analysis of extracted Endoplasmic Reticulum revealed that there was significantly higher amount of MUFA in IDH mutant than wild type. SCD1 expression was increased in IDH mutant compared to wild type due to D2HG-mediated upregulation of SCD1 in IDH mutant. Therefore, IDH mutant in which SCD1 expression level was higher than wild type indicated high sensitivity to SCD inhibitor, and apoptosis was highly induced in IDH mutant compared to wild type. RNA sequencing was performed in U251RH treated with SCD inhibitor compared to U251RH treated with DMSO, and lipid droplet metabolism-associated RNA expression was significantly changed in SCD inhibitor-treated U251RH. Based on the RNA sequence data, we checked lipid droplet in U251RH with presence or absence of SCD inhibitor, and lipolysis was induced by SCD inhibitor treatment, suggesting that SCD inhibition is associated with the apoptosis in IDH mutant via enhanced lipolysis mechanism. CONCLUSIONS D2HG produced in IDH mutant glioma directly induces SCD1 expression and enhances sensitivity to SCD inhibitor, which suggests that SCD inhibitor would be IDH mutant glioma-specific treatment strategy.
STEM-08. MODELING AND UNDERSTANDING GLIOBLASTOMA EDGE CELLS
Authors: Naga Prathyusha Maturi, Ines Neves, Yonglong Dang, Irem Yildirim, Francesco Latini, Tobias Bergström, Anders Sundström, Pengwei Xing, Malin Jarvius, Rolf Larsson, Mårten Fryknäs, Mats Ryttlefors, Xingqi Chen, Fredrik Swartling, Lene Uhrbom
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma is a devastating disease with an overall median survival of 8 months from diagnosis. The majority of patients die of a tumor relapse in close proximity of the resected primary tumor. Glioblastoma is intensely researched but most studies have been performed on tissues and cultures derived from the bulk tumor while it is the remaining edge cells that cause lethality. Investigations of edge cells are rare and few experimental models exist. Here we have established and analyzed a series of matched cell cultures derived from the tumor bulk and outer edge of six IDH wildtype glioblastoma patients with the purpose to understand glioblastoma edge cell biology. Tumor samples were resected guided by 5-ALA fluorescence using neuro-navigation and stringent procedures to not contaminate edge samples with bulk tumor cells. First bulk tumor samples were resected from 5-ALA fluorescent tissue. After removal of all fluorescent areas and careful irrigation of the cavity the edge sample was resected 1-2 cm outside of the fluorescent border in a non-eloquent area. Following dissociation the samples were used in sphere assays and for explantation. There was a significant difference in self-renewal across all patients between matched bulk and edge cultures, in line with results from sphere assays on acute cells, suggesting maintenance of glioblastoma cell properties in established cultures. Invasion analysis showed a reverse significant difference between matched bulk and edge cultures strengthening a general functional distinction between tumor bulk and edge cells across patients. To investigate the molecular basis of our findings we performed whole exome sequencing (WES) and combined single cell RNA- and ATAC-sequencing (10X Multiome). Analyses are ongoing but WES data does not support genetic causes for their differences while the 10X Multiome data indicate that epigenetic regulation may underlie the different properties of bulk and edge glioblastoma cells.
CTNI-58. IMPROVING TRIAL ACCESS FOR PEOPLE WITH RARE CNS TUMORS: AN NCI-CONNECT PHASE I/II TRIAL OF PLX038 IN TUMORS WITH MYC/MYCN AMPLIFICATIONS INCORPORATING CORRELATIVE STUDIES AND PATIENT REPORTED OUTCOMES
Authors: Marta Penas-Prado, Joseph Wooley, Jinkyu Jung, Ying Yuan, Meili Zhang, Laura Baranello, Nicole Briceno, David Levens, Tito Mendoza, Yves Pommier, Craig Thomas, Elizabeth Vera, Daniel Santi, Terri Armstrong, Mark Gilbert
Journal: Neuro-Oncology (2022)

Abstract MYC genes encode transcription factors that regulate expression of genes involved in cell division. Supraphysiologic levels of MYC drive oncogenesis in many human cancers and induce the formation of topoisome complexes, essential to managing the torsional strain that would otherwise oppose transcription and replication. MYC/MYCN amplifications are seen in multiple primary CNS tumors including 30% of relapsed medulloblastomas (MB) and a subtype of ependymoma (EPN) where MYCN amplification defines the tumor. PLX038 is a PEGylated macromolecule containing the topoisomerase I inhibitor SN-38. PEGylations lead to longer half-life, tumor accumulation and decreased toxicity. We hypothesize that PLX038 will be efficacious in primary CNS tumors driven by MYC/MYCN amplifications by targeting the MYC-induced topoisome (Das, S.K. 2022 DOI10.1016/j.molcel.2021.11.016). METHODS Trial in development. Design/Objectives: Phase I (N = 12) – determine the maximum tolerated dose and recommended phase 2 dose of PLX038 in recurrent primary CNS tumors using TITE-BOIN design. Phase II - 3 independent cohorts, N = 30 for each group with interim analysis after 10 each: 2A - MYC-N amplified EPN post resection and radiotherapy (PFS); 2B - Recurrent MYCN amplified EPN or MYC/MYCN amplified MB (disease control rate, DCR); 2C - Other recurrent primary CNS tumors with MYC/MYCN amplifications (DCR). Additional measures: PROs from the Office of Patient-Centered Outcomes Research (OpCORe) web-based early phase trial endpoints; biomarkers of PLX038 distribution and response/resistance in peripheral blood, tumor tissue, hair follicles, and abdominal wall fat pad tissue. CONCLUSIONS NCI-CONNECT’s commitment to innovative designs can mitigate some of the barriers to access experimental therapy for people with rare CNS tumors. This basket trial will enroll participants with unifying molecular features and potential susceptibility to PLX038 despite different histological diagnoses. Furthermore, incorporation of comprehensive PROs will help identify clinical benefit and tolerability while correlative studies in tumor and other tissues will help identify biomarkers of response or resistance.
QOL-13. THE ROLE OF EPILEPSY IN ELDERLY PATIENTS WITH GLIOBLASTOMA: AN AUSTRIAN MULTICENTER ANALYSIS
Authors: Matthias Demetz, Constantin Hecker, Aleksandrs Krigers, Lukas Machegger, Johannes Kerschbaumer, Philipp Geiger, Johannes Pöppe, Antonio Spinello, Christoph Griessenauer, Claudius Thomé, Christian Freyschlag, Christoph Schwartz
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND With an aging population, acquisition of a better understanding of prognostic factors in elderly patients with Glioblastoma multiforme (GBM) is of utmost importance. Epileptic seizures have been found to correlate with improved overall survival (OS) in low-grade gliomas; however, the impact of epilepsy in GBM patients on outcome parameters is poorly defined. This study aims at specifically evaluating the impact of epilepsy in elderly GBM patients. Material &amp; METHODS Two Austrian academic neurosurgical centers retrospectively analyzed all elderly (≥ 65 years) GBM patients with de-novo tumors, who underwent surgery between 09/2006 and 07/2021. Epidemiological, histopathological and survival data were gained from patients’ electronic charts and screened for presence of epilepsy preoperatively or during follow-up. Tumor volume was assessed using standardized software. RESULTS 391 patients (55% males, 45% females) with a median age at surgery of 73 years (IqR 68.5-77.5) were analyzed. The mean predicted OS was 12.4 months (CI95% 10.9-14.0). Mean follow-up was 10.4 months (CI95% 9.1-11.6) in our cohort. Median tumor volume amounted to 26.47 cm3 (IqR 12.65-43.49). 95 patients (24%) suffered from preoperative epilepsy. 17 (18%) patients showed epilepsy after tumor resection. Four patients (1.0%) showed a worsening of already preoperatively diagnosed seizures. Patients with lower tumor volumes experienced significantly more often seizures compared to patients with larger tumors, p&amp;lt; 0.001. Survival did not correlate with preoperative epilepsy (p &amp;gt; 0.05). However, Cox-regression revealed that multifocal tumor location (HR=1.777, p=0.025) and thalamic involvement (HR=11.121, p=0.030) influenced OS. Surgery-associated complications shortened OS significantly (HR=1.945 [CI95% 1,296-2,916], p=0.025). CONCLUSION Even though epilepsy was not found to directly impact survival in elderly GBM patients, we found that surgery led to epilepsy freedom in a significant proportion of our patient cohort, thereby potentially leading to improved QoL. Greatest focus should be set on avoiding any surgery-associated deficits, since these severely influence the OS.
RADT-32. ADJUVANT RADIOTHERAPY VERSUS SURVEILLANCE FOR GRADE 2 INTRACRANIAL MENINGIOMAS: A MULTICENTER STUDY
Authors: Hwa Kyung Byun, Won Ick Chang, Il Han Kim, Joo Ho Lee, Chul-Kee Park, In Ah Kim, Chae-Yong Kim, Chang-Ok Suh, Jaeho Cho, Eui Hyun Kim, Jong Hee Chang, Seok-Gu Kang, Ju Hyung Moon, Hong In Yoon, Chan Woo Wee
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND To compare the outcomes between adjuvant radiotherapy (ART) and surveillance in patients with grade 2 intracranial meningiomas (MNG2s) after surgical resection.Materials and METHODS This multicenter study included 518 patients with newly diagnosed MNG2 who underwent resection between 1998–2018. Patients receiving ART with conventional fractionation (n = 158) were compared with those undergoing surveillance (n = 360). Progression-free survival (PFS) and progression/recurrence (P/R) rates were evaluated. Propensity score matching was performed to adjust for covariables (n = 43 in each group). RESULTS The median follow-up was 64.9 months. The median ART dose was 60 Gy in 30 fractions. Patients receiving ART had larger tumors (median, 5.0 vs. 4.5 cm, P &amp;lt; 0.001) and less frequent gross total resection (69.6% vs. 85.3%, P &amp;lt; 0.001). In multivariable analysis, ART was associated with significantly improved PFS (HR, 0.34; 95% CI, 0.22–0.53; P&amp;lt; 0.001) and P/R (HR, 0.29; 95% CI, 0.18–0.46; P&amp;lt; 0.001). In the propensity score matched cohort, the 5-year PFS rates were 80.8% vs 57.7% (P = 0.020) in the ART and surveillance group, respectively. Even in patients receiving gross total resection, the 5-year PFS (85.0% vs. 64.7%; HR, 0.50; 95% CI, 0.27–0.91; P = 0.023) and P/R rates (15.2% vs. 32.0%; HR, 0.50; 95% CI, 0.25–0.96; P = 0.038) were significantly improved by ART. Using recursive partitioning analysis in patients undergoing surveillance, we classified patients to low-, intermediate-, or high-risk of P/R based on surgical extent, tumor size, and Ki-67 index. The 5-year P/R rates in the low-, intermediate-, and high-risk groups were 18.6%, 37.9%, and 65.3%, respectively. CONCLUSION ART significantly improved PFS and P/R in MNG2s irrespective of surgical extent and should be recommended after both gross total and partial resection. A recursive partitioning analysis model for P/R may guide clinicians for decision making in resected MNG2s.
CTIM-24. NUTMEG: A RANDOMIZED PHASE II STUDY OF NIVOLUMAB AND TEMOZOLOMIDE VERSUS TEMOZOLOMIDE ALONE IN NEWLY DIAGNOSED ELDERLY PATIENTS WITH GLIOBLASTOMA
Authors: Hao-Wen Sim, Zarnie Lwin, Elizabeth Barnes, Kerrie McDonald, Sonia Yip, Roel Verhaak, Amy Heimberger, Merryn Hall, Matthew Wong, Ross Jennens, David Ashley, Mark Rosenthal, Elizabeth Hovey, Benjamin Ellingson, Annette Tognela, Hui Gan, Michael Back, Eng-Siew Koh, Anne Long, Katharine Cuff, Stephen Begbie, Craig Gedye, Anna Mislang, Hien Le, Margaret Johnson, Benjamin Kong, John Simes, Mustafa Khasraw
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Nivolumab is a PD-1 inhibitor with known safety profile. An increase in mutations as we age is well documented in glioblastoma and other cancers. Higher mutational load is associated with increased response to nivolumab in extracranial malignancies. NUTMEG examined the activity of nivolumab added to temozolomide in glioblastoma patients aged ≥ 65 years. METHODS NUTMEG was an international multicenter phase II trial for newly diagnosed glioblastoma patients aged ≥ 65 years, randomized 2:1 to experimental (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide 150-200mg/m2 D1-5 Q28D + nivolumab 240mg D1,15 Q28D C1-4 and 480mg D1 Q28D C5-6) versus standard arm (40Gy/15 fractions with temozolomide 75mg/m2, then 6 cycles of temozolomide alone 150-200mg/m2 D1-5 Q28D), stratified by age, ECOG status, MGMT status and resection extent. RESULTS 103 patients were enrolled (69 in experimental arm, 34 in standard arm). Median age was 73 years, 36% ECOG 0, 57% MGMT-unmethylated and 51% gross macroscopic resection. Median follow-up is 31 months to date, with 77 deaths (surviving patients to continue follow-up and final results will be presented). Median overall survival was 11.8 months in the experimental arm versus 12.0 months in the standard arm (HR 0.95 95%CI 0.59-1.53 for experimental relative to control). Six-month progression-free survival rate using mRANO was 64% in the experimental arm versus 49% in the standard arm (HR 0.81 95%CI 0.51-1.26). Grade 3/4 adverse events were reported in 46% of experimental arm (7% lung infection, 7% thromboembolic events, 6% fatigue, 6% muscle weakness) and in 29% of control arm (9% fatigue, 6% seizure, 6% thromboembolic events). CONCLUSIONS There was insufficient evidence of clinical benefit with nivolumab in this population. No new safety signals were identified. Central imaging review is underway and correlative studies will characterize the immune landscape, including mutational load, neoantigen and other immune markers. NCT04195139.
EXTH-71. CHEMOTACTIC RECOMBINANT ADENO-ASSOCIATED VIRUS (RAAV) VIROTHERAPY IMPROVES LYMPHOCYTE RECRUITMENT IN GLIOBLASTOMA (GBM)
Authors: Christina von Roemeling, Kelena Klippel, Vrunda Trivedi, Oleg Yegorov, Changlin Yang, Lan Hoang-Minh, Bently Doonan, Yong Ran, Todd Golde, Duane Mitchell
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Although immunotherapy holds promise for producing durable outcomes in GBM, a major obstacle is the limited ability of cytotoxic T lymphocytes (CTLs) to home to the tumor. CTLs are recruited via long-range signaling mediated by the diffusion of chemokines present in inflammatory environments. During glioma formation, tumors manufacture immune-suppressive chemokines and cytokines that co-opt resident cells, resulting in the preferential recruitment of immune suppressor cells from the periphery. We explored a novel strategy to selectively reprogram the tumor microenvironment (TME) using focal delivery of rAAV encoding a powerful call-and-receive chemokine for CTLs: CXCL9. HYPOTHESIS: rAAV transduction of the GBM TME to express CXCL9 (rAAV6-CXCL9) will enhance CTL tumor infiltration and improve responsiveness to immunotherapy. METHODS Proteomic arrays were used to identify CTL chemokines absent in human glioma. 3D immunohistochemistry and flow cytometry was used to evaluate geospatial rAAV transgene expression and lymphocyte trafficking in vitro and in vivo. Survival studies of rAAV6-CXCL9 alone and in combination with anti-PD-1 checkpoint blockade was performed in preclinical models of GBM. Tumor immunogenicity following treatment was evaluated by scRNAseq and proteomic analysis. RESULTS We identify rAAV6 as a reliable capsid for transducing murine tumor-reactive astrocytes. Transgene expression following a single intra-tumor injection is focal, stable, and results in high levels of CXCL9 production. CXCL9 is effective at promoting tumor T-cell chemotaxis in vitro and in vivo. rAAV6-CXCL9 treatment sensitizes GBM to PD-1 blockade, improving survival in two distinct syngeneic preclinical models- an effect that is largely dependent on CD8 T-cells. CONCLUSIONS We combine the excellent safety profile of rAAV with focal delivery, enhancing exposure within the tumor compartment and mitigating systemic toxicities seen with conventional therapies. rAAV therapy was successful at stimulating the intended biological response to our encoded transgene (CXCL9): increased lymphocyte recruitment. This strategy has far-reaching potential across other immunotherapy platforms.
CTNI-57. RADIONUCLIDE THERAPY WITH 177LU-DOTATATE (LUTATHERA) IN ADULTS WITH ADVANCED INTRACRANIAL MENINGIOMA - INTERIM ANALYSIS RESULTS OF A SINGLE-ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY
Authors: Sylvia Kurz, Elcin Zan, Christine Cordova, Marissa Barbaro, Andrea Troxel, Joshua Silverman, Matija Snuderl, David Zagzag, John Golfinos, David Kondziolka, Erik Sulman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND While most meningiomas are considered benign tumors, a subset of these tumors are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgical and radiotherapeutic options, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in neuroendocrine tumors. Here we report the results of the interim analysis of an ongoing clinical trial (NCT03971461) that is evaluating the effect of 177Lu-DOTATATE in treating progressive intracranial meningiomas. METHODS In this Simon two-stage design phase II study, adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every eight weeks for four doses. 68Ga-DOTATATE PET-MRI was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass. RESULTS Fourteen patients (F = 11, M = 3) with progressive meningiomas (WHO I = 3, II = 10, III = 1) have been enrolled. Median age was 63.1 (range 49-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, no treatment-limiting toxicities were observed. Six of 14 patients (42%) achieved PFS-6. Radiographically, all six patients had achieved Stable Disease. A functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging was observed in three patients. CONCLUSIONS Treatment with SSTR2-targeting 177Lu-DOTATATE is well tolerated. In this interim analysis, six of 14 patients achieved PFS-6. This exceeds the predefined threshold to continue to stage two of this study. This clinical trial is now open to patient enrollment at two study sites in the US.
TMIC-53. DEVELOPMENT OF A GEO-TAGGED TUMOR SAMPLE REGISTRY; LINKAGE OF TUMOR SAMPLE LOCATION TO IMAGING CHARACTERISTICS
Authors: John Lynes, Sebastian Rubino, Arnold Etame, James Liu, Andre Beer-Furlan, Nam Tran, Alexia Ruiz, Rob Macaulay, Michael Vogelbaum
Journal: Neuro-Oncology (2022)

Abstract Background Significant intra- and inter-heterogeneity exists in gliomas. This provides clinical, radiological, diagnostic, and treatment challenges. To date, there have been few efforts to comprehensively catalog information obtained in the operating room that spatially links neuro-navigation localization to imaging characteristics, gross intraoperative visual findings, and pathological/molecular features. The value of this spatial localization is probably greatest in high grade gliomas, which have been demonstrated to have intra-tumoral histological and genetic/epigenetic heterogeneity. METHODS An IRB-approved institutional registry of patients undergoing clinically-indicated surgery with use of an image-guidance system (IGS) was launched in November 2019 and as of June 1, 2022 includes nearly 500 patients, of which 243 were diagnosed with gliomas. Intraoperatively, locations within the gross tumor or tumor-infiltrated brain were sampled at each surgeon’s discretion, and each sample was linked to their precise location with the IGS system (“geo-tagged”). The registry includes information regarding surgeon; anesthesia technique; use of intraoperative tumor fluorescence; tumor location and volume; pathologic diagnosis and molecular features, and sample number. RESULTS Of 243 gliomas, 26 were low grade and 217 were high grade with 174 being glioblastoma. For enhancing tumors, volume of enhancement ranged from 0.31 to 127.0 cm3 with an average of 22.9 cm3. Tumors were widely distributed throughout the cerebrum with 133 left-sided tumors, 110 right-sided and 32 spanning multiple lobes or deep subcortical structures including the brainstem. 51% of surgeries were under awake anesthesia, and 40% were performed using fluorescence guidance. The average number of navigation image-linked samples collected per tumor was 3.67; 3.48 in low grade gliomas, and 3.69 in high grade gliomas. Samples are archived in frozen and/or formalin-fixed, paraffin-embedded formats for future research. CONCLUSION This registry provides the foundation for correlation of imaging, intraoperative findings, and pathology in brain tumors, and it will support detailed laboratory/translational investigations addressing tumor heterogeneity.
RADT-39. STAGED GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR LARGE INTACT AND RESECTED BRAIN TUMORS; THE MUSC EXPERIENCE
Authors: Edward Duffy, Charlotte Rivers, Maggie Stroud, Michael Hall, Bradley DePaoli
Journal: Neuro-Oncology (2022)

Abstract Stereotactic radiosurgery (SRS) is a well-established treatment modality for management of both benign and malignant central nervous tumors. One limiting factor in the use of SRS is tumor size. Staged radiosurgery treatment is an option to utilize this treatment modality while still limiting associated toxicity. This involves treating each target in 2 separate sessions, spaced apart by approximately 30 days. We describe a series of 17 patients with 20 unique lesions treated using this technique in our department from January of 2019 through December of 2021. 18 treated lesions were malignant brain metastases and 2 were meningiomas. For 13 lesions, SRS was the primary treatment, and for 7 lesions, SRS was adjuvant treatment after surgery. The median target size for fraction 1 was 18.40 cm^3 with a median dose of 12.65 Gy. The median target size for fraction 2 was 14.50 cm^3 with a median dose of 12.08 Gy. All but one target was prescribed to the 50% isodose line. Median follow up was 7.12 months. Local control at the site of treated lesions was 90%. 3 patients with local control at the site of the fractionated treatment were noted to have additional progression within the CNS. There were 2 patient deaths within 30 days of treatment. One death was due to respiratory failure. The other cause of death was unknown. Treatment was well tolerated with no grade 3 or higher acute toxicity. 50% of patients went on to receive additional systemic therapy. 55% of patients are known to have died at the time of latest follow up. Overall, staged gamma knife radiosurgery appears to be an effective option for treating both intact and resected tumors with an acceptable toxicity profile.